First total synthesis of aerucyclamide B Stella Peña, Laura Scarone, Eduardo Manta, Gloria Serra ⇑ Cátedra de Química Farmacéutica, Facultad de Química, Universidad de la República, General Flores 2124, CP 11800 Montevideo, Uruguay article info Article history: Received 13 February 2013 Revised 15 March 2013 Accepted 16 March 2013 Available online 24 March 2013 Keywords: Aerucyclamide Macrocyclization Oxa(thia)zole Hexacyclopeptide abstract The first total synthesis of the antimalarial aerucyclamide B has been achieved in 9% overall yield. Two thiazoles and a dipeptide were used to prepare two open precursors of cyclo-Gly- L-allo-Thr-L-Ile-Thz- D-allo-Ile-Thz. Cyclodehydration with Deoxo-Fluor of the b-hydroxyamide present in the macrocycle, ren- dered aerucyclamide B (67%) and an unexpected fluorous derivative (28%). Ó 2013 Elsevier Ltd. All rights reserved. Cyanobacteria are a rich source of biologically active natural products. Their secondary metabolites show a wide range of bio- logical activities including anticancer, antibacterial, antiparasite, antiviral and protease inhibition activities. 1 The cyanobacterium Microcystis aeruginosa is well-known for the production of the toxic cyclic peptide microcystins. 2 M. aeruginosa also produces several linear peptides that are potent protease inhibitors, 3 and cyclamides which are cyclic peptides composed of alternating heterocyclic amino acids. 4 Aerucyclamides A, B, C, and D were isolated in 2008 by Gademann and co-workers from the toxic freshwater cya- nobacterium Microcystis aeruginosa PCC 7806. 5 The most active of the four was aerucyclamide B (1, Scheme 1), displaying a submi- cromolar IC 50 value against Plasmodium falciparum K1. In addition, this compound displays a large selectivity for the parasite with re- spect to the L6 rat myoblast cell line. 5b Seeking to further explore their biological activity, a synthesis program was initiated to devel- op a convergent route to aerucyclamides and analogs. Herein, we present the total synthesis of aerucyclamide B. Our retrosynthetic analysis is shown in Scheme 1. We planned to obtain first the macrocycle 2 from dipeptide 3, 6 and two thiazole building blocks 4, 7 and 5, 8 by a convergent macrocycle-assembly methodology. This strategy was successfully used by Meyers and co-workers for the synthesis of a structural related product, bistratamide D using three heterocycle building blocks: a thiazole, an oxazole and an oxazoline. 9 In the paper, the authors described some problems related with the deprotection of the functional groups and coupling reactions of the oxazoline ring. In fact, we ob- tained a mixture of decomposition products during the deprotec- 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.03.060 ⇑ Corresponding author. Tel./fax: +598 29290290. E-mail address: gserra@fq.edu.uy (G. Serra). N O N H N S HN N S NH H H O O O H D-allo-Ile L-Ile 1 NH HO N H N S HN N S NH H H O O O H O 2 BocHN N S CO 2 Et BocHN N S MeO 2 C H 3 4 5 NH HO NHBoc H O H O OMe Scheme 1. Retrosynthetic analysis of 1. Tetrahedron Letters 54 (2013) 2806–2808 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet